The Chemical Chaperone, PBA, Reduces ER Stress and Autophagy and Increases Collagen IV α5 Expression in Cultured Fibroblasts From Men With X-Linked Alport Syndrome and Missense Mutations.
| Autor: | Wang D; The University of Melbourne, Department of Medicine (Northern Health and Melbourne Health), Melbourne, Victoria, Australia., Mohammad M; The University of Melbourne, Department of Medicine (Northern Health and Melbourne Health), Melbourne, Victoria, Australia.; Department of Biomedical Science, International Islamic University of Malaysia, Kuala Lumpur, Selangor, Malaysia., Wang Y; The University of Melbourne, Department of Medicine (Northern Health and Melbourne Health), Melbourne, Victoria, Australia., Tan R; The University of Melbourne, Department of Medicine (Northern Health and Melbourne Health), Melbourne, Victoria, Australia., Murray LS; Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Ricardo S; Department of Anatomy and Developmental Cell Biology, Monash University, Clayton, Victoria, Australia., Dagher H; The University of Melbourne, Department of Medicine (Northern Health and Melbourne Health), Melbourne, Victoria, Australia., van Agtmael T; Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Savige J; The University of Melbourne, Department of Medicine (Northern Health and Melbourne Health), Melbourne, Victoria, Australia. |
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| Jazyk: | angličtina |
| Zdroj: | Kidney international reports [Kidney Int Rep] 2017 Mar 27; Vol. 2 (4), pp. 739-748. Date of Electronic Publication: 2017 Mar 27 (Print Publication: 2017). |
| DOI: | 10.1016/j.ekir.2017.03.004 |
| Abstrakt: | Introduction: X-linked Alport syndrome (OMIM 301050) is caused by COL4A5 missense variants in 40% of families. This study examined the effects of chemical chaperone treatment (sodium 4-phenylbutyrate) on fibroblast cell lines derived from men with missense mutations. Methods: Dermal fibroblast cultures were established from 2 affected men and 3 normals. Proliferation rates were examined, the collagen IV α5 chain localized with immunostaining, and levels of the intra- and extracellular chains quantitated with an in-house enzyme-linked immunosorbent assay. COL4A5 mRNA was measured using quantitative reverse transcriptase polymerase chain reaction. Endoplasmic reticulum (ER) size was measured on electron micrographs and after HSP47 immunostaining. Markers of ER stress (ATF6, HSPA5, DDIT3), autophagy (ATG5, BECN1, ATG7), and apoptosis (CASP3, BAD, BCL Results: Both COL4A5 missense variants were associated with reduced proliferation rates on day 6 ( P = 0.01 and P = 0.03), ER enlargement, and increased mRNA for ER stress and autophagy (all P values < 0.05) when compared with normal. Sodium 4-phenylbutyrate treatment increased COL4A5 transcript levels ( P < 0.01), and reduced ER size ( P < 0.01 by EM and P < 0.001 by immunostaining), ER stress (p HSPA5 and DDIT3, all P values < 0.01) and autophagy (ATG7, P < 0.01). Extracellular collagen IV α5 chain was increased in the M1 line only ( P = 0.06). Discussion: Sodium 4-phenylbutyrate increases collagen IV α5 mRNA levels, reduces ER stress and autophagy, and possibly facilitates collagen IV α5 extracellular transport. Whether these actions delay end-stage renal failure in men with X-linked Alport syndrome and missense mutations will only be determined with clinical trials. |
| Databáze: | MEDLINE |
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